A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose
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To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of SB-743921 when administered as a 1-h infusion every 21 days to patients with advanced solid tumors or relapsed/refractory lymphoma.
Patients who failed prior standard therapy or those without any standard options were eligible. Forty-four patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase. An additional 20 patients were enrolled at the recommended phase II dose to obtain additional safety and pharmacokinetic data. The doses evaluated ranged from 2 to 8 mg/m2. The pharmacokinetics of SB-743921 was evaluated at 19 time-points over 48 h following during administration during cycle 1. Toxicity was assessed by the NCI Common Terminology Criteria version 3.0. Response evaluation was performed every 6 weeks.
The most common and consistent DLT was neutropenia. Other DLTs observed included hypophosphatemia, pulmonary emboli, SVC syndrome, transaminitis, hyponatremia, and hyperbilirubinemia. The MTD of SB-743921 as a 1-h infusion every 21 days was established as 4 mg/m2. The maximum plasma concentration and area under the plasma concentration time curve appeared to increase proportionally to dose. One durable objective response was seen in a patient with metastatic cholangiocarcinoma who was on treatment 11 months and 6 patients had stable disease for over four cycles.
The recommended phase II dose of SB-743921 on this specific schedule of a 1-h infusion every 3 weeks is 4 mg/m2. The promising efficacy and lack of severe toxicities in this study warrant the continued development of SB-743921.
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- A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose
Cancer Chemotherapy and Pharmacology
Volume 67, Issue 2 , pp 447-454
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- Phase I
- Kinesin spindle protein
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- Author Affiliations
- 1. University of Wisconsin Carbone Cancer Center, K4/528, 600 Highland Ave., Madison, WI, 53792-5666, USA
- 2. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
- 3. GlaxoSmithKline R&D, Research Triangle Park, NC, USA
- 4. GlaxoSmithKline R&D, Collegeville, USA